Enamel protectant and repair toothpaste

ABSTRACT

Substantially aqueous-free, enamel protectant and enamel repair toothpastes containing: stannous fluoride, calcium and a substantivity agent comprising: an emulsion of polydimethylsiloxane in a nonionic surfactant, wherein: (a) substantivity of said stannous fluoride and calcium into biofilm present on enamel is enhanced through calcium binding shifting from bidentate to monodentate in the presence of stannous fluoride; and (b) said toothpastes indicate substantially improved, enamel protectant factor (EPF) and enamel repair factor (ERF) values compared to fluoride brushing treatments with comparable or higher fluoride levels.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/651,044, which was filed with the U.S. Patent and trademarkOffice on Oct. 12, 2012, entitled “Improved Remineralizing andDesensitizing Compositions, Treatments and Methods of Manufacture”;which specification, includes Examples. Tables and Drawings, are herebyincorporated by reference, in total into the present application. Thisapplication is co-pending with U.S. patent application Ser. No.14/251,284, filed on Apr. 11, 2014, titled “Enamel Protectant and RepairToothpaste Treatments”.

FIELD OF THE INVENTION

The present invention is directed to advances in enamel protectant andenamel repair, aqueous-free, stannous fluoride, toothpastes; whereby theprotectant and repair ingredients are substantive to enamel surfaces,thereby extending the protecting and repairing processes with improvedstannous fluoride effectiveness. Key protectant and repair combinationsfor the toothpastes of the present invention comprise: stannous fluorideand calcium in aqueous-free, substantivity agents.

BACKGROUND OF THE INVENTION

The use of fluoride in anticaries drug products, marketed in the U.S.,is carried out under the guidance of the FDA's Fluoride Monograph, 21CFR 355.10 (revised Apr. 1, 2012).

TABLE 1 Concentration and Dosage of Stannous Fluoride inDentifrice/Rinse/Gel products according to the Federal Register 21 CFR355.10 Dentifrices Dentifrices containing 850 to 1,150 ppm theoreticaltotal fluorine in a gel or paste dosage form. Stannous fluoride 0.351 to0.474% with an available fluoride ion concentration = 700 ppm forproducts containing abrasives other than calcium pyrophosphate. Stannousfluoride 0.351 to 0.474% with an available fluoride ion concentration =290 ppm for products containing the abrasive calcium pyrophosphate.Preventive Stannous fluoride 0.4% in an anhydrous glycerin gel, madetreatment from anhydrous glycerin and the addition of suitable gelthickening agents to adjust viscosity. Treatment Stannous fluorideconcentrate marketed in a stable form and rinse containing adequatedirections for mixing with water immediately before using to result in a0.1% aqueous solution.Dentrifices

Fluoride dentifrices have been shown in numerous clinical trials to beeffective anticaries agents [Stookey, J. Dent. Res. 1990, 69(SpecialIssue): 805-812] and have been recognized as a major cause of theremarkable decline in caries prevalence in many developed countries.Dentifrices have been widely adopted around the world as the principlemeans of delivering topical fluoride and obtaining caries preventivebenefits.

“Washout” of various enamel protectant and enamel repair ingredientsfrom enamel surfaces by saliva flow, eventually controls the effectiveresidence time of various commercial fluoride, enamel protectant andenamel repair, brushing compositions. To improve enamel protectant andenamel repair effectiveness, commercial, professionally prescribed,fluoride, brushing compositions resort to high levels of fluoride, i.e.5000 ppm for Rx toothpastes, gels and rinses and to approximately 22,000ppm fluoride for “in-chair”, professionally applied varnishes. Inaddition, standard OTC, fluoride toothpastes can contain up to 1500 ppmfluoride under the FDA's Fluoride Monograph.

The current market for fluoride brushing products includes: professionaland consumer, oral care, fluoride treatments, both OTC and Rx brushingproducts; including: toothpastes, gels, pastes and varnishes. As notedabove, Rx fluoride toothpastes and Rx fluoride toothpastes are welloutside fluoride Monograph levels containing up to 5000 ppm fluoride.Professional oral care, in-chair, fluoride varnishes contain up to about22,000 ppm fluoride, while OTC fluoride toothpastes can contain up to1500 ppm fluoride, the maximum level provided for the Monograph.

The American Dental Association (ADA); the Food & Drug Administration(FDA) and oral care professionals including: general practitioners,periodontists, orthodontists, pediatric dentists, etc. as a group; aregenerally concerned over the trend of increasing fluoride levels. Theseorganizations and oral care professionals generally favor using lowerlevels of fluoride in various in-chair treatments and various OTC andRx, oral care, home treatments for patients, provided . . . enamelprotection and repair, achieved with lower fluoride levels, arecomparable to the results reported for brushing products with higherlevels of fluoride. This preference for lower fluoride-brushing productsis driven by the concern over toxicity, fluorosis in children, etc.,associated with exposure to high fluoride levels, long term.

It is generally accepted, approximately 90% of the fluoride used in OTCand Rx, fluoride, brushing treatments is expectorated after use. Thus,the window for fluoride treatment of enamel is essentially limited tothe time fluoride is being brushed onto the enamel. In contrast,fluoride varnishes containing 22,000 ppm fluoride, applied to the enamelby an oral care professional, are designed to maintain substantivefluoride levels on the enamel after patient expectoration.

Fluoride varnishes are generally applied professionally, at a frequencyof about once every six months with the target audience comprisingprimarily children.

Dietary fluoride levels have gradually increased due to fluoridateddrinking water and the fluoride in water used in food preparation, etc.In addition, most consumers use fluoride: toothpastes, rinses, gels,etc. Extensive literature citations indicate topical fluoride treatmentsare more effective in protecting and repairing enamel than treatmentwith systemic fluorides.

See: Ripa, Public Health Dent., 1991; 51:23-41.

Yet, with all this fluoride available, caries continues to pose achallenge: in children, as well as adults including coronal caries inthe elderly, caries in dry mouth patients, caries in immunocompromisedpatients, caries in patients undergoing medical or dental treatment,etc.

There is a need to improve enamel protectant and enamel repaireffectiveness for professional oral care, fluoride treatments, as wellas for OTC fluoride products for patient use, while reducing the riskassociated with exposure to high fluoride levels.

Additionally, there is a need to improve the efficacy of fluorideproducts in the area of enamel protection and enamel repair, where theefficacy of various fluoride treatments is assessed as a function of thefluoride level used to effect treatment of various conditions of theenamel.

OBJECTS OF THE PRESENT INVENTION

To provide stannous fluoride toothpastes with improved enamel protectantfactor (EPF) values and improved enamel repair factor (ERF) values.

To provide stannous fluoride toothpastes with improved EPF and ERFvalues, where improvements in EPF and ERF values are accompanied byreduced fluoride content in the toothpastes.

To reduce fluoride levels in toothpastes, while attaining comparable orimproved EPF and ERF values, compared to current, commercial, fluoridebrushing products, as well as fluoride brushing products described inthe prior art.

To improve EPF and ERF values for the enamel of “at-risk” patients.

To improve enamel conditions of “at-risk” patients includingimmunocompromised patients; cancer therapy, cardio treatment, diabetes,COP patients; etc.

DEFINITION OF TERMS

The following terms used throughout this specification and claims todescribe features of the toothpastes of the present invention aredescribed below:

“Aqueous-free” is defined as: substantially free from water.

“Enamel Protectant Factor (EPF)” is defined as: the percent reduction inenamel solubility divided by the fluoride level in parts per millionusing FDA method #40.

“Enamel Repair Factor (ERF)” is defined as: the average increase inenamel fluoride concentration divided by the fluoride level of thefluoride brushing product tested using FDA method #33.

“Toothpaste” is defined as: an abrasive-based paste suitable foradministration of stannous fluoride to enamel surfaces by brushing witha toothbrush.

“Mucoadhesive” is defined as: a substance that is retained for a periodof time onto surfaces in the mouth that is not easily removed by themechanical action of the tongue nor by flow of saliva.

“Stable stannous fluoride” is defined as: compositions that, whenchemically assayed, substantially retains the level of stannous and/orfluoride in an unreacted state.

“Biofilm” is defined as: a surface adherent film comprised of bacteria,exuded polysaccharides, etc., that is not easily removed by mechanicalmeans or saliva flow.

“Substantivity agent” is defined as: a composition that improves themucosal retention of the desired agents.

“Cation bridging” is defined as: electrical attraction between two filmsor membranes initiated by cation moieties.

“Shift in calcium binding from bidentate to monodentate” is defined as:the loss of “chelate”-like binding by calcium cations with acorresponding increase in single ligand binding by calcium cations.

“Nonionic surfactant” is defined as: a composition that indicatessurface active properties with the absence of charged species.

“CaF+ moiety” is defined as: a monodentate calcium fluoride ion.

“Linear, polymeric, polycarboxylates, substantivity enhancer” is definedas: a linear polymer with carboxylate substituents that increasesretention of compositions onto charged surfaces.

“Emulsion discontinuous phase” is defined as: the minor component in anemulsion that is surrounded by a continuous phase.

“Emulsion continuous phase” is defined as: an emulsion component thatsurrounds discontinuous phase component.

SUMMARY OF THE INVENTION

The present invention is directed to aqueous-free, toothpastecompositions and associated methods for treatment and methods ofmanufacture, wherein the toothpastes contain stannous fluoride frombetween 850 and about 1500 ppm fluoride, in an aqueous-free,substantivity agent. The toothpastes of the present invention protectand repair enamel more effectively than toothpastes and toothpastecompositions containing comparable or substantially higher levels offluoride, as indicated by comparative EPF and ERF values reportedherein.

The unexpected enamel protectant and enamel repair features of thestannous fluoride toothpastes of the present invention, as detailedbelow in the Examples, Tables and Drawings; are attributed to unique,aqueous-free, toothpaste compositions, which feature:

stannous fluoride at fluoride levels from between about 850 and about1500 ppm fluoride and calcium;

a substantivity agent;

cation bridging associated with microbial fluoride binding; and

a pH of at east about 4.0, when the toothpastes are administered toenamel in the presence of saliva.

The enamel protectant and enamel repair, toothpaste compositions of thepresent invention, when brushed onto enamel, form substantive,mucoadhesive gels on enamel in the presence of saliva; whichmucoadhesive gels gradually release the stannous fluoride onto enamel.This slow release continues until the mucoadhesive gel is eventuallytotally solubilized by saliva. This gradual release minimizes the“wash-out” effect traditionally experienced with fluoride brushingproducts. The resultant enamel protectant and enamel repair increases inEPF and ERF values, resulting from the extended enamel residence time ofstannous fluoride, calcium and cation bridging associated with microbialfluoride binding to biofilm. This improved stannous fluoride efficiencyreduces risks associated with elevated fluoride levels.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 of the Drawings summarizes comparative, in vitro, enamelprotectant factor (EPF) values for enamel treated with a toothpaste ofthe present invention with stannous fluoride at 1150 ppm fluoride;compared with: (a) an Rx 5000 ppm, sodium fluoride toothpaste, and (b)an OTC, 900 ppm, stannous fluoride toothpaste.

FIGS. 2 through 5 of the Drawings illustrate enamel repair factor (ERF)values for toothpastes of the present invention with compositions, asdescribed in Examples 1 through 5, with stannous fluoride at: 1100, 1148and 1150 ppm stannous fluoride compared with toothpastes having stannousfluoride at 1100 ppm and sodium fluoride at 900 ppm or sodium fluorideat 5000 ppm, respectively.

FIGS. 2 through 5 present ERF values for toothpastes of the presentinvention comprising compositions, as described in Examples 1 through 5.These toothpastes of the present invention contain stannous fluoride atlevels of: 1100, 1148 and 1150 ppm stannous fluoride, compared with: (a)a 900 ppm sodium fluoride toothpaste, and (b) an 1100 ppm stannousfluoride toothpaste, (c) a 5000 ppm sodium fluoride toothpaste or (d) a900 ppm fluoride toothpaste.

FIGS. 2 through 5 of the Drawings illustrate enamel repair factor (ERF)for toothpastes of the present invention with compositions as describedin Examples 1 through 5. These toothpastes of the present inventioncontain stannous fluoride at levels of: 1100, 1148 and 1150 ppm stannousfluoride compared with 1000 ppm stannous fluoride toothpaste, 900 ppmsodium fluoride toothpaste and 5000 ppm sodium fluoride toothpaste.

DETAILED DESCRIPTION OF THE INVENTION

Aqueous-free, stannous fluoride, toothpastes of the present inventioncomprise substantivity agents that contain various enamel protectant andenamel repair ingredients. These substantivity agents function ascarriers for various enamel protectant and repair ingredients. Thesesubstantivity agents are characterized by their ability, in the presenceof saliva, to form mucoadhesive gels which are substantive to enamelwith biofilm. These substantive, mucoadhesive gels are furthercharacterized by their ability to: (a) gradually dissolve when exposedto saliva flow, and (b) gradually release various enamel protectant andenamel repair ingredients onto enamel surfaces with biofilm as theydissolve. This gradual dissolution feature of these mucoadhesive gelsminimizes saliva “wash-out” of enamel protectant and enamel repairingredients by gradually releasing these ingredients onto enamelsurfaces with biofilm. The substantivity agents of the present inventionextend the duration of enamel protectant and enamel repair treatmentsand support cation bridging associated with microbial fluoride binding,thereby enhancing the EPF and ERF values of various toothpastes of thepresent invention, while simultaneously reducing the level of fluoriderequired to achieve the unexpected increases in EPF and ERF values.

In as preferred embodiment of the invention, calcium and phosphatecomponents are included in the toothpastes. These are described by MingTung in U.S. Pat. Nos. 5,037,639; 5,268,167; 5,427,768; 5,437,857;5,460,803; 5,562,895; by Tung in the American Dental AssociationFoundation publication, “ACP Technology,”; by Schemehorn, et. al., inThe Journal of Clinical Dentistry Vol. XXII: No 2. 51-54, 2011; by the19 references cited by Schemehorn, et. al.; and by the description ofvarious Gantrez® resins containing calcium, including Gantrez® M955available from International Specialty Products, Wayne, N.J., USA.

The aqueous-free, substantivity agents of the present invention hold thevarious enamel protectant and enamel repair ingredients, includingstannous fluoride, calcium and phosphate components, in a conditionwhere these ingredients remain stable and unreacted. When thisaqueous-free, substantivity agent is exposed to saliva, it forms amucoadhesive gel that is substantive to enamel with biofilm. Thismucoadhesive gel continues to hold the enamel protectant and enamelrepair ingredients onto enamel surfaces with biofilm without theingredients reacting. These ingredients eventually react upon beingreleased onto saliva and biofilm coated, enamel surfaces.

Eventually, this mucoadhesive, substantivity agent is totally dissolvedby saliva, releasing the balance of unreacted enamel protectant andenamel repair ingredients onto saliva and biofilm coated, enamelsurfaces.

Aqueous-free, toothpastes of the present invention contain enamelprotectant and enamel repair ingredients, suitable for protecting andrepairing dental enamel; wherein:

said aqueous-free, toothpastes inhibit premature reaction of the enamelprotectant and enamel repair ingredients;

the enamel protectant and enamel repair ingredients are introduced ontoenamel with biofilm via saliva that solubilizes substantivity agentsthat are substantive to: enamel, dentin, biofilm and pellicle;

the enamel protectant and enamel repair ingredients contained in thesubstantivity agents are gradually released onto the enamel in anunreacted state as the saliva soluble, substantivity agent undergoessaliva dissolution at rates, which are controlled by saliva flow and thecomposition of the substantivity agent; and

bidentate binding of calcium shifts to monodentate binding of calcium inthe presence of stannous fluoride.

For purposes of the present invention, saliva soluble, aqueous-freeemulsions used as substantivity agents include those emulsions that arecomprised of polydimethylsiloxane polymers in nonionic surfactants, asdescribed in U.S. Pat. Nos. 5,032,387; 5,098,711; 5,538,667; 5,651,959;having the structural formula:HO[(C2H4O)x/(C3H6O)y]-[C3H6O]z-[(C2H4O)x/(C3H6O)y]Hwherein the sum of x, y and z is between 120 and 150. In a preferredembodiment, x=76, y=0 and z=56.

Preferred aqueous-free, saliva soluble emulsions for use assubstantivity agents of the present invention include aqueous-freeemulsions comprising a nonionic surfactant continuous phase and adiscontinuous phase of polydimethylsiloxane (PDMS) at viscositiesranging from between about 1500 cs and about 2.5 million cs.Particularly preferred, aqueous-free emulsions include a nonionicsurfactant continuous phase and a discontinuous phase PDMS atviscosities between 10,000 cs and 2.5 million cs.

Preferred polydimethylsiloxanes are selected from the group consistingof polydimethylsiloxane: at 1500 cs, at 10,000 cs, at 100,000 cs, at250,000 cs, at 500,000 cs, at 750,000 cs, at 1.5 million cs, at 2.2million cs, at 2.5 million cs and combinations thereof.

Foam modulators are useful in the present invention. These include,without limitation: materials operable to control amount, thickness orstability of foam generated by the composition (e.g., dentifricecomposition) upon agitation. Any orally acceptable, foam modulator canbe used, including polyethylene glycols (PEGs), also known aspolyoxyethylenes. High molecular weight PEGs are suitable, includingthose having an average molecular weight of about 200,000 to about7,000,000, for example about 500,000 to about 5,000,000 or about1,000,000 to about 2,500,000. One or more PEGs are optionally present ina total amount of about 0.1% to about 10%, for example about 0.2% toabout 5% or about 0.25% to about 2%.

Humectants useful for the present invention include, without limitation:polyhydric alcohols such as glycerin, sorbitol, xylitol or low molecularweight PEGs. In various embodiments, humectants can prevent hardening ofthe toothpastes upon exposure to air. In various embodiments, humectantsalso function as sweeteners.

Any other desired components may be added to the compositions,including, for example, additional: mouth-feel agents, pH modifyingagents, flavorants, sweeteners, additional anticalculus and Antiplaqueagents, abrasives, polishing agents, antimicrobial (e.g. antibacterial)agents such as those described in U.S. Pat. No. 5,776,435, salivastimulants, anti-inflammatory agents, H2 antagonists, nutrients,vitamins, proteins, antioxidants, colorants, or additional activematerials useful for the prevention or treatment of a condition ordisorder of hard or soft tissue of the oral cavity, the prevention ortreatment of a physiological disorder or condition, or to provide acosmetic benefit

Tables 2 through 8 summarize:

EPF and ERF data for toothpastes of the invention at varyingcompositions, as described in Examples 1 through 5, compared withcommercial, fluoride, brushing products;

Actual Examples of toothpastes of the invention;

Illustrative Examples of toothpastes of the invention; and

Illustrative Treatments with toothpastes of the invention.

In a preferred embodiment of the invention, the toothpastes of thepresent invention contain ingredients that substantially effect enamelprotection factor (EPF) and enamel repair factor (ERF) values. Theseinclude:

Stannous fluoride and calcium,

Phosphate components, and

Substantivity agents and substantivity enhancers, including: mixedsodium and calcium salt copolymers of methyl/vinyl/ether/maleic acid;

where the stannous fluoride, calcium and phosphate components remainunreacted and the pH of the toothpaste when administered to salivacoated enamel is at least about 4.

The foregoing ingredients are described in detail below.

Stannous Fluoride Concentration

The amount of stannous fluoride in the toothpastes of the presentinvention, applied to the toothbrush (dose) is not as important as theconcentration of available stannous fluoride in the toothpaste.Heretofore, reducing fluoride concentration in brushing products hasbeen reported not to be as effective as regular concentration fluorideproducts.

Petersson, et. al., Swed. Dent. 1982, 6:233-238

Metropoulos, et. al., Community Dent. Health, 2002, 1:193-200.

The extraordinary EPF and ERF values of the toothpastes of the presentinvention allow for reducing stannous fluoride concentrations whileeffecting acceptable fluoride protection and uptake results.

The fluoride dose is important in regard to enamel fluorosis in childrenunder six years of age, due to fluoride toothpaste ingestion. For thisreason, reducing the amount of stannous fluoride applied with thetoothpastes of the present invention is a preferred strategy overlowering the dose of stannous fluoride toothpastes of the inventionintended for use by children under six years of age.

While fluoride brushing products have a long history of safety, there isa continuing concern associated with dental fluorosis due to fluorideingestion in children under age six. See: Dendrys, J. Am. Dent. Assoc.2000, 131(6): 746-755.

Studies have shown that for children 1-3 years of age, 30 to 75% of thefluoride brushing product is ingested; and for children 4-6 years ofage, 14 to 48% is ingested. Warren and Levy, Pediatr. Dent., 199,21:265-271.

Stannous fluoride toothpastes of the present invention, with theirimproved efficacy can be used at reduced stannous fluoride levels, andthereby substantially lower the risk of overdosing and the onset offluorosis, while delivering effective EPF and ERF results.

See also Zero, BMC Oral Health, 2006, 6(Suppl 1): 59; 1-13.

Monitoring the Fluoride-Mineral Phase Formed on Enamel as a Function ofthe Concentration of Fluoride Ions [F⁻] in the Demineralizing Medium

See: Mohammed, et. al., Caries Res., 2013; 47:421-428.

-   -   At below 45 ppm [F⁻] in the solution ¹⁹F MAS-NMR showed        fluoride-substituted apatite formation, 1B ¹⁹F magic angle,        spinning nuclear magnetic resonance was used to characterize the        solid phase precipitated on enamel as a function of fluoride        concentration during exposure of the enamel to an in vitro        demineralization system. The cariostatic effect of fluoride is        due to the formation of F_(s)a HAP and CaF₂ depending on the        [F⁻] level in the solution.    -   Above 45 ppm, calcium fluoride (CaF₂) formed in increasing        proportions    -   Further increases in [F⁻] caused no further reduction in        demineralization, but increased the proportion of CaF₂ formed.    -   As to the mechanism of fluoride anticaries efficacy . . .        fluoroapatite formation in enamel is investigated.        Advantages of ¹⁹F MAS-NMR:    -   (1) selectively probes the local environment of only fluorine        atoms in the sample, permitting direct identification of the        possible structural forms in which [F⁻] may exist within the        enamel.    -   (2) detects all fluorine present, whether:        -   crystalline,        -   amorphous, or        -   adsorbed.    -   (3) measures very low concentrations of fluoride on the order of        0.1%. ¹⁹F MAS-NMR established the effects of varying fluoride        concentrations on fluoride-enamel interactions under acidic        conditions using bulk enamel blocks rather than powder.

For the samples demineralized in the presence of [F⁻]:

-   -   (1) chemical shifts were identified;    -   (2) formulation of fluoride-substituted apatite:        ^((a))(Ca₁₀CPO₄)₆F_(2-x),        (F_(s)-HAP); and    -   (3) formation of CaF2;        -   were observed in the aged portion at 45 ppm [F⁻] solutions,        -   At [F⁻] above 45 ppm less F_(s)-HAP forms and an increased            signal for CaF, and        -   For [F⁻] above 136 ppm mostly CaF₂ was identified.

The present study demonstrates that the addition of fluoride producesFs-HAP as a major chemical species only at low concentrations offluoride.

There is overwhelming evidence that low fluoride levels found in:

-   -   (a) saliva can significantly reduce enamel demineralization, and    -   (b) plaque has the potential to remineralize even at pH values        typically regarded as demineralizing.

Calcium CaF₂, CaF⁺ and Phosphate

-   -   Christoffersoni, et. al., in ACTA ODONTOL. SCAND. 1988,        46:325-336, reports:    -   “It is suggested that the calcium fluoride-like material formed        on dental enamel during treatment of enamel with acidified        solutions of high fluoride content is a phosphate-containing        calcium fluoride.”    -   “The aims of the present work are to determine the rates of        growth and dissolution of pure calcium fluoride in aqueous        suspensions and possible mechanisms controlling these processes,        and to study the properties of the calcium fluoride-like        material formed by adding fluoride to systems containing        hydroxyapatite crystals and/or dissolved calcium and phosphate,        simulating the type of calcium fluoride-like material formed on        dental enamel as a result of topical treatment with acidified        solutions of high fluoride content.”    -   “From our results of dissolution of pure CaF2 in systems        containing phosphate it can be seen that 1 μm phosphate has a        dramatic effect on the rate of dissolution of CaF2.”    -   “The calcium fluoride-like materials containing phosphate appear        to be more likely candidates to serve as slow fluoride release        agents.”    -   B. Øgaard's “CaF2 Formation: Cariostatic Properties and Factors        of Enhancing the Effect,” Caries Res., 2001; 35 (Suppl)        11:40-41, teaches:    -   “CaF2 or a CaF2-like material/phosphate-contaminated CaF2 is a        major reaction product during topical treatment of dental hard        tissues. Recently, evidence has suggested that CaF2 is formed        not only on surfaces but also to some extent in the enamel. The        minimum concentration of fluoride required for CaF2 formation is        not well known and may depend on whether calcium is available        from plaque fluid or only through dissolution of the dental hard        tissue. Furthermore surface adsorption of fluoride to crystals        may cause local concentrations necessary for CaF2 formation. It        has been suggested that CaF2 acts as a pH-controlled reservoir        of fluoride. The rate-controlling factor appears to be        phosphate, which controls the dissolution rate of CaF2 at high        pH. Increasing fluoride concentration, prolonging the exposure        time or using a fluoride solution with low pH can increase CaF2        formation. CaF2 formed at low pH contains less internal        phosphate which has been shown to be less soluble. This may be        of clinical significance for fluoride applied topically a few        times per year.”    -   “The interaction between the fluoride ion and dental hard        tissues has been investigated extensively since modern fluoride        research started in the 1940s. The chemistry of this process is        complicated due to many impurities in hydroxyapatite-like        carbonate and magnesium and to a large variety of fluoride        concentrations, pH and composition of the agents used in caries        prevention. During pH cycling in plaque, fluoride may exchange        with hydroxyl in the apatite and a series of solids with        intermediate composition and crystallographic properties are        formed known as fluorhydroxyapatite.”

“CaF2 is the major or probably the only reaction product on dental hardtissues from short treatments with relatively concentrated fluorideagents (Cruz et. al., Scand. J. Dent. Res., 1992; 100:154-158). Withoutdoubt, this pH-controlled depot of CaF2 plays a major role in thecariostatic effect of topical fluoride. CaF2 has been detected on dentalhard tissues weeks and months after a single topical fluoride treatment(Caries Res., 1991, 25:21-26) and is the only logical way to explainthat such treatments have a cariostatic effect. By treating enamelsamples subjected to topical fluoride treatment with KOH, thecariostatic effect is lost (Øgaard, et al., J. Dent. Res., 1990,69:1505-1507).”

-   -   J. M. ten Cate's “Review on Fluoride, with special emphasis on        calcium fluoride mechanisms in caries prevention”, Eur. J. Oral        Sci., 1997, 105:461-465, teaches:    -   “For treatments to be effective over periods longer than the        brushing and the following salivary clearance, fluoride needs to        be deposited and slowly released. Calcium fluoride (or like)        deposits act in such a way, owing to a surface covering of        phosphate and/or proteins, which makes the CaF2 less soluble        under in vivo conditions than in a pure form in inorganic        solutions. Moreover, due to the phosphate groups on the surface        of the calcium fluoride globules, fluoride is assumed to be        released with decreasing pH when the phosphate groups are        protonated in the dental plaque.”    -   “In the presence of low concentrations of fluoride in solution        (such as saliva or plaque fluid), hydroxyapatite might be        dissolved below the critical pH (for hydroxyapatite), but the        released mineral ions could be reprecipitated as fluoroapatite        or a mixed fluor-hydroxyapatite. This mechanism prevents the        loss of mineral ions, while providing additional protection to        mineral crystallites by laying fluoride-rich other layers onto        the apatite crystallites.”    -   “These observations point to the presence of slowly releasing        fluoride reservoirs, either on the dentition or the mucosal        surfaces. Recent work has shown that in particular the oral        mucosa, both by its chemical and morphological nature and the        large surface area, is an underestimated retention site of        fluoride.”    -   “Research has shown that small amounts of fluoride in plaque and        saliva are sufficient to shift the de, remineralization balance        favorably. Such levels should then be available throughout the        day, in particular during periods of carbohydrate fermentation        in the plaque. A fluoride-releasing reservoir system, effective        at low pH, such as shown for calcium fluoride, would be a        preferred system.”    -   Vogel, et al., in “No Calcium-Fluoride-Like Deposits Detected in        Plaque shortly after a Sodium Fluoride Mouthrinse”, Caries Res.,        2010; 44:108-115, reported:    -   “Plaque ‘calcium-fluoride-like’ (CaF2-like) and fluoride        deposits held by biological/bacterial calcium fluoride (Ca—F)        bonds appear to be the source of cariostatic concentration of        fluoride in plaque fluid. The aim of this study was to quantify        the amounts of plaque fluoride held in these reservoirs after a        sodium fluoride rinse.”    -   “The results suggest that either CaF2-like deposits were not        formed in plaque or, if these deposits had been formed, they        were rapidly lost. The inability to form persistent amounts of        CaF2-like deposits in plaque may account for the relatively        rapid loss of plaque fluid fluoride after the use of        conventional fluoride dentifrices or rinses.”    -   “Based on laboratory [Margolis and Moreno, J. Dent. Res., 1990,        69 (Spec. Issue) 606-613; J. Am. Dent. Assoc., 2000, 13:887-889;        and clinical observations (reviewed by Featherstone, J. American        Dent. Assoc., 2000, 13:887-889; the current models for        increasing the anticaries effects of fluoride (F) agents        emphasize the importance of maintaining a cariostatic        concentration of F in oral fluids.”    -   “This inability to form potentially more persistent calcium        fluoride deposits, which appears to be due to the low        concentration of oral fluid Ca, may account for the relatively        rapid loss of F in plaque after the use of current        over-the-counter topical F agents. It should be noted in this        regard that (1) studies in which a Ca preapplication was used to        ameliorate this situation have produced very large and        persistent increases in both plaque fluid and that salivary        fluoride (Vogel, et. al., Caries Res., 2006, 40:449-454; Vogel,        et. al., Caries Res. 2008 (a) 421; 401-404; and Vogel, et.        al., J. Dent. Res. 2008(b) 87:466-469; and that (2) preliminary        studies (unpubl.) using modifications of the techniques        described here confirm that the use of a Ca prerinse prior to a        F rinse indeed forms large amounts of CaF2-like deposits.”

Substantivitv Agents

For purposes of the present invention, substantivity agent refers to acomposition or combination of compositions that, when administered tooral cavity surfaces with biofilm, enhance the retention of stannousfluoride and calcium to said biofilm containing oral cavity surfaces.

The unexpected enamel protectant and enamel repair features of theaqueous-free, stannous fluoride toothpastes of the present invention areattributed to the unique substantivity properties indicated by thetoothpastes of the invention.

For purposes of the present invention, preferred substantivity agentsfor the stannous fluoride toothpastes of the present invention includevarious aqueous-free emulsions of polydimethylsiloxane/polymers innonionic surfactants at viscosities of at least about 10,000 cs.

These substantivity agents form mucoadhesive gels in the presence ofsaliva, which are substantive to biofilm-coated enamel and graduallydissolve under saliva flow, releasing stannous fluoride onto the biofilmon the enamel at a pH of at least about 3; thereby effecting EPF and ERFvalues of at least about 2.5 and about 200, respectively.

For purposes of the present invention, substantivity agents includesaliva soluble, aqueous-free emulsions comprised of:

polydimethylsiloxane polymers in solid, nonionic surfactants, asdescribed in U.S. Pat. Nos. 5,032,387; 5,098,711; 5,538,667; 5,645,841;5,651,959; having the following structural formula:HO[(C₂H₄O)_(x)/(C₃H₆O)_(y)]—[C₃H₆O]_(z)—[(C₂H₄O)_(x)/(C₃H₆O)_(y)]Hwherein y=0 and the sum of x and z is between 120 and 150. In apreferred embodiment, x=76, y=0 and z=56.

Preferred aqueous-free, saliva soluble emulsions for use in thesubstantivity agents of the present invention include aqueous-freeemulsions comprising a nonionic surfactant, continuous phase and adiscontinuous phase of polydimethylsiloxane (PDMS) at viscositiesranging from between about 1500 cs and about 2.5 million cs.Particularly preferred are aqueous-free emulsions with a nonionicsurfactant continuous phase and a discontinuous PDMS phase atviscosities between 10,000 cs and 2.5 million cs.

Preferred polydimethylsiloxanes are selected from the group consistingof polydimethylsiloxane: at 1500 cs, at 10,000 cs, at 100,000 cs, at250,000 cs, at 500,000 cs, at 750,000 cs, at 1.5 million cs, at 2.2million cs, at 2.5 million cs and combinations thereof.

In a preferred embodiment of the invention, copolymers described beloware useful as substantivity enhancers; when combined with theaqueous-free, substantivity agents of the present invention. Thesesubstantivity enhancers include various linear polymeric,polycarboxylates, such as: copolymers of sodium and calcium salts ofmethyl/vinyl/ether/maleic acid including those copolymers availablecommercially as Gantrez® MS-955 polymer, a mixed sodium and calcium saltof methyl/vinyl/ether/maleic acid copolymer; where the cations form saltbridges which cross-link the polymer chains.

The chemical structure of this copolymer is represented by the followingchemical structure:

where m is an integer that provides molecular weight for the polymerbetween about 60,000 and about 500,000.

Preferred are 1:4 to 4:1 copolymers of maleic anhydride or acid withanother polymerizable ethylenically unsaturated monomer, preferablymethyl vinyl ether (maleic anhydride) having a molecular weight of about30,000 to about 1,000,000.

Sodium and calcium salts of carboxymethyl cellulose ether polymers canalso be used including sodium and calcium salts of carboxymethylcellulose ether, hydroxyethyl cellulose ether, sodium cellulose ether,etc.

The contribution of Ca++ from the copolymer substantivity enhancer toERF values is illustrated in FIGS. 5 and 6 of the Drawings and Tables 6and 7.

Examples 1 Through 5

The following stannous fluoride toothpaste samples were prepared, asdescribed below, and subsequently tested for EPF and/or ERF values, asdescribed in Tables 1 through 8 and FIGS. 1 through 5 below:

Example 1

A 5 liter Ross/Olsa vacuum mixer kettle with internal homogenizer washeated to 60 degrees C. while the vessel was charged with 592.225 gm ofanhydrous glycerin. Crodasinic L, 53.5 gm and TEGO betaine, 53.5, wereadded and homogenized at 1500 RPM for 10 minutes under vacuum. Then942.1 gm of PEG 400 was added along with ULTRAMULSION® [poloxamer 407(80%)] and 2.5 million cs polydimethylsiloxane (20%), 64.5 gm, withhomogenizer speed at 1500 rpm for 10 minutes. Additional glycerin,592.225 gm, was added along with acesulfame K, 21.0 gm, titaniumdioxide, 53.5 gm, calcium sulfate, 97.0 gm, micronized (20 micron)sodium phosphate monobasic, 17.4 gm, and Gantrez MS-955, 107.5 gm. Thehomogenizer at 1500 rpm was begun and continued for 15 minutes undervacuum. The contents were cooled to 25 degrees C. and 1.64% stannousfluoride in glycerin, 1443.5 gm, was added to the kettle. Thehomogenizer was set at 1000 rpm under vacuum for 10 minutes and stopped.To the kettle was added Sident 22S, 650 gm, and Zeodent 113, 268 gm,with the anchor stirrer at medium speed. Sucralose, 4.5 gm, was addedand the homogenizer set at 1000 rpm for 5 minutes under vacuum.Vanillamint, 33 gm, and Multisensate flavor, 4.55 gm, were added andhomogenized at 1000 rpm for 5 minutes. The homogenizer stopped and theanchor stirrer continued for 10 minutes with cooling to 25 degrees C.The contents was dispersed into tubes for use. Upon dispensing, thetoothpaste indicated a pleasant taste with no stannous fluorideaftertaste.

Example 2

In a stainless steel 500 mL mixing vessel, using an overhead stirrer,34.26 gm of PEG 400 were added along with 49.406 gm of glycerin, and57.74 gm of 1.64% stannous fluoride in glycerin. Stirring was begun at alow speed while heating to 80° C. Then 2.58 gm of poloxamer 407/2.5million cs (10%) ULTRAMULSION® substantivity agent was added withstirring for 15 minutes. The overhead stirrer speed was increased tomedium and 4.3 gm of Gantrez MS-955 substantivity enhancer was addedwith stirring for 5 minutes. Then Crodasinic L, 2.14 gm; Sucralose,0.344 gm; and acesulfame K, 1.074 gm were added with continued stirringfor 10 minutes. TEGO betaine CKD, 2.14 gm, was added and stirred for 5minutes. Calcium fumarate, anhydrous, micronized, 2.84 gm, was addedwith stirring for 5 minutes followed by addition of sodium dihydrogenphosphate, anhydrous, micronized, 0.696 gm, was added with continuedstirring for 5 minutes.

In multiple increments, Sident 22S, 26.0 gm was added with stirring 2minutes between each addition. When the Sident 22S was all added, thenZeodent 113, 10.72 gm added with stirring continuing for 15 minutesafter which vanillamint, 2.14 gm, spearmint, 1.074 gm, TiO2, 2.14 gm,ICE1500, 0.16 gm, and Multisensate flavor, 0.250 gm, were added withcontinued stirring for 5 minutes. The stirrer was removed and thetoothpaste was added to dispensing tubes. When used as a toothpaste, apleasant, refreshing mouthfeel and very little metallic taste isperceived.

Example 3

In a stainless steel 500 mL mixing vessel, using an overhead stirrer,32.26 gm of PEG 400 were added along with 45.446 gm of glycerin, and57.74 gm of 1.64% stannous fluoride in glycerin. Stirring was begun at alow speed while heating to 80° C. Then 2.58 gm of poloxamer 407/2.5million cs (10%) ULTRAMULSION® substantivity agent was added withstirring for 15 minutes. The overhead stirrer speed was increased tomedium and 4.3 gm of Gantrez MS-955 substantivity enhancer was addedwith stirring for 5 minutes. Then Crodasinic L, 2.14 gm; Sucralose,0.344 gm; and acesulfame K, 1.074 gm were added with continued stirringfor 10 minutes. TEGO betaine CKD, 2.14 gm, was added and stirred for 5minutes. Calcium lactate gluconate, anhydrous, micronized, 8.8 gm, wasadded with stirring for 5 minutes followed by addition of sodiumdihydrogen phosphate, anhydrous, micronized, 0.696 gm, was added withcontinued stirring for 5 minutes.

In multiple increments, Sident 22S, 26.0 gm was added with stirring 2minutes between each addition. When the Sident 22S was all added, thenZeodent 113, 10.72 gm added with stirring continuing for 15 minutesafter which vanillamint, 2.14 gm, spearmint, 1.074 gm, TiO2, 2.14 gm,ICE1500, 0.16 gm, and Multisensate flavor, 0.250 gm, were added withcontinued stirring for 5 minutes. The stirrer was removed and thetoothpaste was added to dispensing tubes. When used as a toothpaste, apleasant, refreshing mouthfeel and very little metallic taste isperceived.

Example 4

In a stainless steel 500 mL mixing vessel, using an overhead stirrer,35.18 gm of PEG 400 were added along with 47.446 gm of glycerin, and57.74 gm of 1.64% stannous fluoride in glycerin. Stirring was begun at alow speed while heating to 80° C. Then 2.58 gm of poloxamer 407/2.5million cs (10%) ULTRAMULSION® substantivity agent was added withstirring for 15 minutes. The overhead stirrer speed was increased tomedium and 4.3 gm of Gantrez MS-955 substantivity enhancer was addedwith stirring for 5 minutes. Then Crodasinic L, 2.14 gm; Sucralose,0.344 gm; and acesulfame K, 1.074 gm were added with continued stirringfor 10 minutes. TEGO betaine CKD, 2.14 gm, was added and stirred for 5minutes. Calcium sulfate, anhydrous, 3.88 gm, was added with stirringfor 5 minutes followed by addition of sodium dihydrogen phosphate,anhydrous, micronized, 0.696 gm, was added with continued stirring for 5minutes.

In multiple increments, Sident 22S, 26.0 gm was added with stirring 2minutes between each addition. When the Sident 22S was all added, thenZeodent 113, 10.72 gm added with stirring continuing for 15 minutesafter which vanillamint, 2.14 gm, spearmint, 1.07 gm, TiO2, 2.14 gm,ICE1500, 0.16 gm, and Multisensate flavor, 0.250 gm, were added withcontinued stirring for 5 minutes. The stirrer was removed and thetoothpaste was added to dispensing tubes. When used as a toothpaste, apleasant, refreshing mouthfeel and very little metallic taste isperceived.

Example 5

A 5 liter Ross/Olsa vacuum mixer with internal homogenizer was heated to80 degrees C. while the vessel was charged with 942.1 gm of PEG 400,1184.45 gm of anhydrous glycerin and 1443.5 gm of 1.64% stannousfluoride/glycerin. Anchor stirring at slow speed was begun and continuedfor 7 minutes. ULTRAMULSION® [poloxamer 407 (80%)] and 2.5 million cspolydimethylsiloxane (20%), 64.5 gm, was added with homogenizer speedadjusted to 2500 rpm for 15 minutes. The anchor stirrer was increased tomedium speed and Gantrez MS-955, 107.5 gm, was added with stirring andhomogenizing for 5 minutes. Crodasinic L, 53.5 gm, was added withcontinued stirring for 5 minutes. TEGO Betaine CKD, 53.5 gm, was addedand stirring continued for 5 minutes. Micronized (20 micron D50) calciumsulfate, anhydrous, 97 gm, was added with stirring for 5 minutes.Micronized (20 micron) sodium phosphate monobasic, anhydrous, 17.4 gm,was added with stirring for 5 minutes. Sident 22S, 650 gm, was added inincrements at 2 minutes between additions until all was added. Stirringwas continued for 15 minutes.

Vanillamint flavor, 33 gm, and spilanthes extract, 4.55 gm, were addedwith continued stirring for 5 minutes. The vessel was cooled to ambienttemperature over 15 minutes. The contents were dispensed into tubes foruse. Upon dispensing, the toothpaste indicated a pleasant taste with nostannous fluoride aftertaste. Stannous fluoride stability testing wasperformed on the product which exhibited a stable characteristic

In Vitro Testing

In vitro determination of EPF values attributed to administration ofvarious fluoride containing: toothpastes and a test, stannous fluoridetoothpastes onto human enamel subjected to acid challenge.

The following study was carried out according to the FDA Monograph onAnticaries Drug Products for over-the-counter, human use. The study wasperformed following FDA good laboratory practices.

Purpose of the following in vitro study: to determine the effect of acidchallenge to human enamel treated with various fluoride containingbrushing products. The effect of the acid challenge was established bymeasuring the resistance of enamel specimens treated with variousfluoride brushing products to an acid challenge; before and aftertreatment with various fluoride brushing products.

Tooth Preparation:

Three sound human molars were placed in a disc of red boxing wax so thatonly the enamel surfaces were exposed. Twelve set of three teeth eachwere prepared for the study. All specimens were cleaned and polishedwith a flour of pumice slurry and a rag wheel to remove any deposits orstains.

Preparation of Buffered Lactic Acid Challenge Solution:

Two moles (203.58 g of 88.5% pure lactic acid were diluted withapproximately 500 ml of distilled water. To this was added a solution of84 g NaOH dissolved in about 600 ml of distilled water. The total volumewas then adjusted to 2000 ml. This was the buffered 1.0 M lactic acidchallenge solution.

Another lactic acid solution was prepared by diluting two moles lacticacid to 2000 ml with distilled water. The solution of lactic acid andsodium hydroxide was placed in a 4000 ml beaker, and pH electrodesplaced in the solution. The 1.0 M lactic acid solution was used toadjust the pH of the buffered solution to 4.5. To obtain a 0.1 workingconcentration (for all decalcifications) the 1.0 M buffer was diluted bya factor of 10 with distilled water. Another lactic acid solution wasprepared by diluting two moles lactic acid to 2000 ml with distilledwater. The solution of lactic acid and sodium hydroxide was placed in a4000 ml beaker, and pH electrodes placed in the solution. The 1.0 Mlactic acid solution was used to adjust the pH of the buffered solutionto 4.5. To obtain a 0.1 working concentration (for all decalcifications)the 1.0 M buffer was diluted by a factor of 10 with distilled water.

Deprotection:

Before every use, any residual anti-solubility protection afforded bythe previous treatment was eliminated. Deprotection of these specimenswas accomplished by etching the teeth in the above prepared 0.1M lactatebuffer solution for a two-hour period. Each disc of three specimens wasagitated (450 rpm) in about 50 ml of lactate buffer at room temperatureduring the deprotection period. The teeth were rinsed well withdistilled water immediately following deprotection.

Pre-Treatment Etch:

The test was performed using preheated (37° C.) tooth sets and lactatebuffer. The deprotected tooth sets were mounted on ¼ inch diameteracrylic rods with molten red boxing wax. Multiplaced stirrers were usedfor treatments and the etches. All slurries and solutions werepre-heated to 37° C. The actual treatments and etches were carried outon the bench top with the preheated solutions. Plastic specimencontainers (120 ml) were used for the etching procedure. A ¼ inch holewas drilled in each container lid to accommodate the plastic rod towhich the tooth sets were mounted. A 40 ml portion of 0.1M lactic acidbuffer was placed in each container along with a one-inch magneticstirring bar. The rod of the first tooth set was pushed through the holein the lid, placed in the first container and adjusted so that allenamel surfaces were immersed into the buffer solution. The containerwas then placed on the first magnetic stirrer and stirring was begun.The timer was started at this time. At 30-second intervals the othertooth sets were started in the same manner. After 15 minutes of exposureto the buffered lactate solution, the first set was stopped and the lidand tooth set immediately removed from the container and placed in atray of distilled water to terminate etching. The other sets weresimilarly removed at 30 second intervals in the same order that theywere initiated and the lactate buffer solutions was retained forphosphorus analysis. The tooth sets were placed back in the 37° C. waterbath in preparation for the fluoride treatment step.

Treatment:

The treatments were performed using slurries of the fluoride brushingproducts. The slurries consisted of 1 part fluoride brushing product and3 parts preheated (37° C.) distilled water (9 g:27 ml). Each slurry wasmixed for exactly one minute after adding the water. The slurries wereNOT prepared ahead of time. They were NOT centrifuged. All tooth setswere treated at the same time (one for each fluoride brushing product).The treatment procedure was similar to the etching procedure with theexception of the slurry in place of the acid. A 30 ml portion of thepreheated fluoride brushing slurry was added to the first tooth set, theteeth were immersed in the slurry and the container placed on the firststirrer. The stirrer and timer were started. At 90-second intervals (toallow time for stirring), the other tooth sets were started in the samemanner. At the end of the five minutes of treatment, the first set wasstopped, the tooth set removed and rinsed well with distilled water. Theother sets were removed at 90-second intervals and rinsed well. Thetreatment fluoride brushing slurries were discarded.

Post-Treatment:

A second acid exposure was then performed by the same method as thepre-treatment etch and the lactate buffer solutions were again retainedfor phosphorus analysis. The pre and post-treatment solutions wereanalyzed using a Klett-Summerson Photoelectric Colorimeter.

Repeat Analyses:

The tooth sets were deprotected and the procedure repeated additionaltimes so that each fluoride brushing product was treated and assayed oneach tooth set. The treatment design was a Latin Square design so thatno treatment followed another treatment consistently.

Calculation of Enamel Solubility Reduction:

The percent of enamel solubility reduction was computed as thedifference between the amount of phosphorus in the pre and post acidicsolutions, divided by the amount of phosphorus in the pre solution andmultiplied by 100.

Treatment Groups:

A. Placebo (deionized water)

B. Positive control, MI Paste Plus with fluoride @ 900 ppm fluoride

C. Positive control, ClinPro® 5000 Toothpaste with sodium fluoride at5000 ppm fluoride

D. Test, stannous fluoride toothpaste at 1150 ppm fluoride compositionas described hereinafter in Example 1.

Statistical Analyses:

Statistical analyses of the individual means were performed with aone-way analysis of variance model using Sigma Stat (3.1) Software.Since the ANOVA indicated significant differences, the individual meanswere analyzed by the Student Newman-Keuls (SNK) test.

Results and Discussion:

The deionized water negative control was not effective in reducingenamel solubility. The positive fluoride containing controls and thetest toothpaste were significantly more effective than the deionizedwater negative control. The Clinpro 5000® toothpaste was slightly,significantly more effective than the negative control. The testtoothpaste was dramatically superior to the two positive controls (by afactor of 10).

The results are shown in Table 2 below:

TABLE 2 ENAMEL SOLUBILITY REDUCTION Summary of Results Pre-EtchPost-Etch Delta Percent Group Treatment μP μP μP Reduction EPF ** ADeionized Water  680 ± 16* 780 ± 19 −100 ± 15 −15.03 ± 2.35  B MI PastePlus 677 ± 28 697 ± 19  −20 ± 20  3.92 ± 2.83 0.4 (@ 900 ppm fluoride) CClinpro 5000 ® (sodium 702 ± 20 582 ± 14 120 ± 9 16.96 ± 0.83 0.34fluoride @ 5000 ppm) D Test Toothpaste (stannous 717 ± 18 359 ± 11  358± 18 49.71 ± 1.62 4.3 fluoride @ 1150 ppm fluoride) See Example 1 *Mean± SEM (N = 12) ** To establish the enamel protection factor (EPF) valuesfor each fluoride brushing product tested, the percent reduction inenamel solubility was divided by the fluoride level in parts per millionof the brushing product tested. The resultant number was multiplied by100.

See FIG. 1 of the Drawings.

In Vitro Determination of ERF Values Attributed to Administration ofVarious Fluoride Containing Toothpastes and a Test Toothpaste ontoIncipient Enamel Lesions in Bovine Enamel.

The following study was carried out according to the FDA Monograph onAnticaries Drug Products for over-the-counter, human use, following FDAgood laboratory practices.

Purpose of the following in vitro study: to determine the fluorideuptake into incipient enamel lesions in bovine incisors, treated withvarious fluoride containing, brushing products.

The test procedure was identical to the procedure identified asProcedure 40 in the FDA anticaries Monograph, except the lesions wereformed using a solution comprising 0.1 M lactic acid and 0.2% Carbopol907, wherein the solution was saturated with HAP (hydroxyapatite) at apH of 5.0.

The fluoride uptake was established by analyzing fluoride and calciumlevels of enamel pre-treatment and enamel post-treatment to determinethe change in enamel fluoride attributed to treatment with fluoridecontaining brushing products.

Procedure:

Sound, upper, central, bovine incisors were selected and cleaned of alladhering soft tissue. A core of enamel 3 mm in diameter was preparedfrom each tooth by cutting perpendicularly to the labial surface with ahollow-core diamond drill bit. This was performed under water to preventoverheating of the specimens. Each specimen was embedded in the end of aplexiglass rod (¼″ diameter×2″ long) using methylmethacrylate. Theexcess acrylic was cut away exposing the enamel surface. The enamelspecimens were polished with 600 grit wet/dry paper and then micro-fineGamma Alumina. The resulting specimens were a 3 mm disk of enamel withall but the exposed surface covered with acrylic. Twelve specimens pergroup were prepared. Each enamel specimen was then etched by immersioninto 0.5 ml of 1M HCIO4 for 15 seconds. Throughout the etch period, theetch solutions were continuously agitated. A sample of each solution wasthen buffered with TISAB (fluoride ion probe buffer) to a pH of 5.2(0.25 ml sample, 0.5 ml TISAB and 0.25 ml 1N NaOH) and the fluoridecontent of the solution determined by comparison to a similarly preparedstandard curve (1 ml std+1 ml TISAB). For use in depth of eachcalculation, the Ca content of the etch solution was determined bytaking 50 μl and analyzing for Ca by atomic absorption (0.05 ml qs to 5ml). These data was the indigenous fluoride level of each specimen priorto treatment.

The specimens were once again ground and polished as described above. Anincipient lesion was formed in each enamel specimen by immersion into a0.1M lactic acid/0.2% Carbopol 907 solution for 24 hours at roomtemperature. These specimens were then rinsed well with distilled waterand stored in a humid environment until used.

The treatments were performed using slurries of the various fluoridecontaining brushing products. The flurries consisted of 1 part fluoridecontaining brushing product and 3 parts distilled water (9 g:27 ml).Each slurry was mixed for exactly one minute after adding the water. Theslurries were NOT prepared ahead of time. They were NOT centrifuged. The12 specimens of each group were then immersed into 25 ml of theirassigned slurry with constant stirring (350 rpm) for 30 minutes.Following treatment, the specimens were rinsed with distilled water. Onelayer of enamel was then removed from each specimen and analyzed forfluoride and calcium as outlined above (i.e. 15 second etch). Thepretreatment fluoride (indigenous) level of each specimen was thensubtracted from post treatment, fluoride value to determine the changein enamel fluoride due to the last treatment.

Statistical Analyses:

The results are shown on attached tables. All raw data (individualspecimen Enamel Fluoride Uptake (EFU) values are reported. In addition,the mean, S.D. (standard deviation) and SEM (scanning electronmicrograph) for each group was calculated. Statistical analysis wereperformed by a one-way analysis of variance model using Sigma StatSoftware (3.1). Since significant differences are indicated, theindividual means were analyzed by the Student Newman Keuls (SNK) test.

Test Products:

The test fluoride containing toothpastes were coded as follows:

-   -   1. The test fluoride containing toothpastes were coded as        follows:    -   2. Placebo (deionized water)    -   3. Positive Control MI Paste Plus with 900 ppm fluoride    -   4. Positive Control 2 Clinpro 5000® with sodium fluoride at 5000        ppm fluoride    -   5. Test Toothpaste with stannous fluoride at 1150 ppm fluoride        composition as described in Example 1.        Results:

The results are shown in Table 3 below:

TABLE 3 Change in Incipient Lesion Enamel Fluoride Content EnamelFluoride Concentration (ppm) Fluoride Containing Pre Post BrushingProduct Treatment Treatment Increase Etch Depth ERF** Placebo, deionizedwater  39 ± 3*  47 ± 4  8 ± 3 16.19 ± 0.45 — MI Paste Plus 38 ± 3 323 ±9 285 ± 8 15.84 ± 0.42 31 @ 900 ppm fluoride OTC SnF₂ Paste @ 5000 ppm37 ± 3 1716 ± 22 1679 ± 23 11.30 ± 0.10 34 sodium fluoride Clinpro5000 ® @ 5000 ppm 37 ± 3 2616 ± 54 2579 ± 54 14.55 ± 0.36 51 sodiumfluoride Test Toothpaste @ 1150 ppm 39 ± 2  6459 ± 451  6420 ± 451 13.23± 0.31 540  stannous fluoride See Example 1 *Mean ± SEM (N = 12) **Toestablish the enamel repair factor (ERF) values for each fluoridebrushing product tested, the increase in enamel fluoride concentrationwas divided by the fluoride level of the fluoride brushing product. Theresultant number was multiplied by 100.

See FIG. 2 of the Drawings.

In vitro determination of ERF values attributed to administration ofvarious fluoride containing: toothpastes and a test toothpaste ontoincipient enamel lesions in human enamel was carried out following theEnamel Fluoride protocol described above for the results reported inTable 2. Some of the fluoride containing brushing products tested inthis fluoride uptake study are different than those reported on in Table3 above.

The results are shown in Table 4 below:

TABLE 4 Change in Incipient Lesion Enamel Fluoride Content Pre-TreatmentPost-Treatment Enamel Depth of Enamel Depth of Change in Fluoridecontaining Fluoride Etch Fluoride Etch Depth of Brushing ProductConcentration (microns) Concentration (microns) Etch ERF* Crest ® Tooth1 31 45 692 30 33 PRO- Tooth 2 25 76 1111 35 55 HEALTH ® Tooth 3 134 311320 14 54 Toothpaste Average 1008 47 92 (Stannous Std Dev 314 12Fluoride, 1100 ppm fluoride) Toothpaste Tooth 1 95 80 679 21 74 withSodium Tooth 2 124 72 654 23 68 Fluoride @ Tooth 3 207 41 1140 13 68 900ppm Average 824 70 91 fluoride Std Dev 273 3 Test Tooth 1 165 44 438 2347 Toothpaste Tooth 2 93 61 388 26 57 (Stannous Tooth 3 104 56 723 28 50Fluoride, Average 516 51 50 1100 ppm Std Dev 181 5 fluoride) See Example2 *To establish the enamel repair factor (ERF values for each fluoridebrushing product tested, the average increase in Enamel FluorideConcentration (post treatment) was divided by the fluoride level of thefluoride brushing product tested. The resultant number was multiplied by100.

See FIG. 3 of the Drawings.

TABLE 5 Change in Incipient Lesion Enamel Fluoride Content EnamelFluoride Concentration (ppm) Fluoride Containing Pre Post BrushingProduct Treatment Treatment Increase Etch Depth ERF** Placebo, deionizedwater  41 ± 4* 89 ± 5 47 ± 5 17.88 ± 0.70 — Crest ® PRO-HEALTH ® 44 ± 51530 ± 69  1486 ± 66  10.06 ± 0.25 140 Toothpaste (stannous fluoride,1100 ppm fluoride) Test Toothpaste (stannous 47 ± 5 4857 ± 338 4815 ±338 13.36 ± 0.26 420 fluoride at 1148 ppm fluoride) See Example 4 *Mean± SEM (N = 12) **To establish the enamel repair factor (ERF) values foreach fluoride brushing product tested, the average increase in enamelfluoride concentration (post treatment was divided by the fluoride levelof the fluoride brushing product tested. The resultant number wasmultiplied by 100).

See FIG. 4 of the Drawings

TABLE 6 Change in Incipient Lesion Enamel Fluoride Content EnamelFluoride Concentration (ppm) Fluoride Containing Pre Post BrushingProduct Treatment Treatment Increase Etch Depth ERF** Placebo, deionizedwater  41 ± 4*  89 ± 5  47 ± 5 17.88 ± 0.70 — Crest ® PRO-HEALTH ® 44 ±5 1530 ± 69 1486 ± 66 10.06 ± 0.25 140 Toothpaste (stannous fluoride,1100 ppm fluoride) Test Toothpaste (stannous 52 ± 6 1948 ± 68 1902 ± 7015.28 ± 0.56 166 fluoride at 1148 ppm fluoride) See Example 3 *Mean ±SEM (N = 12) **To establish the enamel repair factor (ERF) values foreach fluoride brushing product tested, the average increase in enamelfluoride concentration (post treatment was divided by the fluoride levelof the fluoride brushing product tested. The resultant number wasmultiplied by 100).

See FIG. 5 of the Drawings

TABLE 7 Illustrative Examples of Toothpastes Stannous Calcium andphosphate Substantivity Agent, Example Fluoride level components,Composition and % by wt. pH of GEL in No. in ppm fluoride % by wt. ofToothpaste of Toothpaste saliva 7 970 Calcium Sulfate, 2.0% F-127/2.5mmCS PDMS(30%) 5.8 NaH2PO4, 0.35% 1.75% 8 900 Calcium Sulfate, 2.2%F-108/12,500CS PDMS(10%) 6.2 NaH2PO4, 0.35% 2.0% 9 1000 Calcium Sulfate,2.5% F-127/600KCS PDMS(30%) 5.5 NaH2PO4, 0.25% 2.2% 10 1100 CalciumSulfate, 2.8% F-127/2.5 mmCS PDMS(10%) 4.8 NaH2PO4, 0.38% 1.65% 11 970Calcium fumarate, 3.0% F-108/600KCS PDMS(20%) 5.7 NaH2PO4, 0.33% 1.4% 12900 Calcium fumarate, 2.8% F-108/2.5 mmCS PDMS(20%) 6.3 NaH2PO4, 0.30%2.3% 13 1000 Calcium fumarate, 1.5% F-127/12,500CS PDMS(30%) 5.6NaH2PO4, 0.15% 1.3% 14 1148 Calcium sulfate, 1.94% F-127/2.5 mmCSPDMS(20%) 4.5 NaH2PO4, 0.348% 1.29% 15 970 Calcium gluconate, 2.2%F-108/2.5 mmCS PDMS(26%) 5.9 NaH2PO4, 0.25% 2.0% 16 900 Calciumfumarate, 2.4% F-127/2.5 mmCS PDMS(15%) 6.3 NaH2PO4, 0.25% 2.2% *Mean ±SEM (N = 12) **To establish the enamel repair factor (ERF) values foreach fluoride brushing product tested, the average increase in enamelfluoride concentration (post treatment was divided by the fluoride levelof the fluoride brushing product tested. The resultant number wasmultiplied by 100).

TABLE 8 Change in Incipient Lesion Enamel Fluoride Content SpecificToothpaste Frequency of Duration of “At-risk” Patient RecommendedTreatment Treatment Caries Stannous Fluoride: 970 ppm Once daily for 2To be determined by fluoride minutes followed oral care professionalsPDMS/Surfactant by expectorating Emulsion: PDMS 800,000 cs Calcium andPhosphate component: 3.2% by wt. EPF: at least about 1.8 ERF: at leastabout 140 pH = 4.9 Undergoing medical Stannous Fluoride: At least twicedaily Duration of and/or professional 1150 ppm fluoridemedical/professional oral care treatments PDMS/Surfactant oral caretreatment with prescribed Emulsion: PDMS medications 800,000 cs Calciumand Phosphate component: 3.8% by wt. EPF: at least about 2.2 ERF: atleast about 180 pH = 3.8 Immunocompromised Stannous Fluoride: 900 ppm Atleast three times Duration of with chronic fluoride dailymedical/professional conditions PDMS/Surfactant oral care treatmentEmulsion: PDMS 600,000 cs Calcium and Phosphate component: 3.4% by wt.EPF: at least about 2.4 ERF: at least about 165 pH = 4.7 Diabetes, heartStannous Fluoride: At least twice daily To be determined by disease,etc. 1100 ppm fluoride oral care professionals PDMS/Surfactant Emulsion:PDMS 2.5 mm CS Calcium and Phosphate component: 3.0% by wt. EPF: atleast about 2.1 ERF: at least about 230 pH = 4.6 Cancer treatmentStannous Fluoride: At least twice daily Duration of 1150 ppm fluoridemedical/professional PDMS/Surfactant oral care treatment Emulsion: PDMS2.5 mm CS Calcium and Phosphate component: 3.2% by wt. EPF: at leastabout 2.3 ERF: at least about 200 pH = 4.3 *Mean ± SEM (N = 12) **Toestablish the enamel repair factor (ERF) values for each fluoridebrushing product tested, the average increase in enamel fluorideconcentration (post treatment was divided by the fluoride level of thefluoride brushing product tested. The resultant number was multiplied by100).

Discussion of EPF and ERF Values Established by In Vitro Testing

Preferred, stannous fluoride toothpastes of the present invention showsubstantial improvement in EPF and ERF values compared to commercialtoothpastes at various fluoride loads as reported in Tables 2 and 8 andFIGS. 1 and 5 of the Drawings.

For example, the ERF values, reported in Table 2 and FIG. 2 for MI PastePlus, OTC Stannous Fluoride paste and Clinpro 5000® Toothpaste are 31,34 and 50, respectively, compared to an ERF for the stannous fluoridetoothpaste of the present invention described in Example 1 of 540. This10× plus improvement in ERF value over commercial toothpastes representsa major advance in fluoride uptake and enamel hardening effectiveness.Such an advantage in enamel hardening efficiency is particularlycritical to patients experiencing: rampant caries, coronal caries,cancer therapy treatments, mucositis treatments, immune deficiencytreatments, bone marrow transplants, etc.

Proposed Mechanism of Action of the Compositions of the PresentInvention

The enamel protectant and/or enamel repair (EPF and/or ERF) datareported for formulations described in Examples 1 through 5, as detailedin Tables 1 through 8 and in FIGS. 2 through 5 of the Drawings, suggestthe substantivity of stannous fluoride and calcium to the biofilmpresent on enamel surfaces is enhanced by a shift from bidentate tomonodentate calcium binding in the presence of stannous fluoride. Thisshift in calcium binding in the presence of stannous fluoride results ina most effective binding site configuration. See:

The enamel protectant and/or enamel repair (EPF and/or ERF) datareported for formulations described in Examples 1 through 5, as detailedin Tables 1 through 8 and in FIGS. 2 through 5 of the Drawings, suggestthe substantivity of stannous fluoride and calcium to the biofilmpresent on enamel surfaces is enhanced by a shift from bidentate tomonodentate calcium binding in the presence of stannous fluoride. Thisshift in calcium binding in the presence of stannous fluoride results ina most effective binding site configuration. See:

-   Dudey and Lim, J. Phys. Chem B, 2004, 108:4546.-   Vogel, et. al., Caries Res., 2010, 94:108-115.-   Rolla and Bowen, Scand. J. Dent. Res., 1977; 85:149-151.-   Rose, et. al., J. Dent. Res., 1993; 72:78-84.    See also:    -   Turner, et. al., Ceramics, Silikaty 57(1):1-6 (2013)        -   Mohammed, et. al., Caries Res., 47:421-428 (2013)

Calcium-Bridge, Fluoride Binding

Calcium binding to biofilm shifts from a bidentate chelation to amonodentate chelation in the presence of fluoride, freeing up Calcium+to bind with fluoride, CaF+ pairs, thereby doubling the calcium bindingcapacity.

Stable fluoride in the toothpastes of the present invention producesmarked reduction in calcium binding affinity and approximately doublescalcium binding capacity. In the absence of fluoride, calcium binding tobiofilm is bidentate. Stable fluoride in the toothpastes of the presentinvention compete with biofilm causing calcium binding to biofilm tobecome monodentate. This allows the binding of about double the quantityof calcium and of CaF+ bound to biofilm. Release of fluoride bound bycalcium bridging into biofilm fluid as a result of fluoride clearanceinto saliva will be accompanied by a corresponding release of calciumwhich, in turn, potentiates the cariostatic effect of fluoride asindicated in the in vitro testing described in Tables 2 through 8 andFIGS. 1 through 5 of the Drawings.

At least some of the stable fluoride present in the toothpastes of thepresent invention is bound to calcium ions (sourced from various calciumsalts in the present invention and/or calcium present in the copolymersubstantivity enhancer, such as Gantrez® MS-955). These calcium ions, inturn, are bound to biofilm associated with enamel.

A drop in pH follows exposure of plaque to sucrose which removes someanionic groups by neutralization, thereby liberating calcium andfluoride (as CaF+) at the very sites where these moieties can do themost good.

The effectiveness of the toothpastes of the present invention depends onthree factors:

substantivity of the formulation to biofilm,

stannous fluoride as the source of CaF+, and

retention of fluoride in a form on biofilm which allows release of CaF+ions into hydroxyapatite.

Stannous fluoride produces a marked reduction in calcium bindingaffinity accompanied by an approximate doubling of the calcium bindingcapacity. In the absence of fluoride, divalent cation binding to plaqueis bidentate. Fluoride competes with macromolecular anionic groups,causing binding to become monodentate. Release of fluoride formed bycalcium bridging, is accompanied by release of calcium, whichpotentiates the cariostatic effect of fluoride.

-   -   The presence CaF+ is required to deliver the enamel protection        and repair (EPF and ERF) results required for the toothpaste        formulations of the present invention.

Summary as to the Role of Cation Bridging in Microbial Fluoride Binding

Fluoride binding produces a marked reduction in calcium bindingaffinity, along with a doubling of calcium binding capacity. Thisindicates that calcium binding changes from bidentate to monodentate.This shift from bidentate to monodentate is a consequence of fluoridereplacing an anionic group as one of the calcium ligends.

The anionic groups to which calcium is no longer bound are then free tobind a CaF+ ion pair, resulting in a doubling of the calcium bindingcapacity. Release of fluoride, bound by calcium bridging into plaquefluid, may be accompanied by a release of calcium which will potentiatethe cariostatic effect of fluoride.

CaF+ is taken up by hydroxyapatite and is responsible for the EPF andERF in vitro data reported for the compositions of the presentinvention. The ERF values reported in Tables 2 through 8 and FIGS. 2through 5 of the Drawings suggest that the CaF+ moiety is incorporatedinto the hydroxyapatite lattice during remineralization.

The toothpastes of the present invention set a new, oral care STANDARDfor Enamel Protection and Enamel Repair, while dramatically reducingexposure to elevated levels in various fluoride varnishes, gels andtoothpastes.

What is claimed is:
 1. An aqueous-free, enamel protectant and enamelrepair, toothpastes containing: stannous fluoride and calcium in asubstantivity agent selected from emulsions of polymethylsiloxanes innonionic poloxamer surfactants, wherein: (a) Substantivity of saidstannous fluoride and calcium into biofilm present on enamel is enhancedthrough a shift in calcium binding from bidentate to monodentate in thepresence of stannous fluoride; and (b) EPF and ERF values of at least2.5 and 200, respectively, are achieved with periodic administration ofsaid toothpastes onto enamel surfaces with biofilm present; (c) whereinthe stannous fluoride is present in an amount of 400-1100 ppm; (d)wherein the composition has a pH of 3-5.8; (e) wherein the calciumcontent is 0.5-5.0%; (f) wherein the calcium is limited to one or moreof calcium fumarate, calcium sulfate, calcium gluconate, and mixedsodium and calcium salts of methyl/vinyl/ether/maleic copolymersthereof; and (g) wherein said nonionic poloxamer is selected from solidand liquid, nonionic poloxamers and combinations thereof.
 2. Acomposition according to claim 1, wherein some of said stannous fluorideand calcium is present as Car.
 3. A composition according to claim 1,wherein said substantivity agent contains linear, polymericpolycarboxylate, substantivity enhancers.
 4. Substantially aqueous-free,enamel protectant and enamel repair, toothpastes according to claim 3,containing stannous fluoride and calcium in a substantivity agentcomprising an emulsion of polydimethylsiloxane polymer at viscositiesfrom between about 10,000 cs and about 2.5 million cs as thediscontinuous phase in a nonionic surfactant, continuous phase. 5.Toothpastes, according to claim 4, wherein nonionic poloxamersurfactants, suitable for said toothpastes, are represented by thestructural formula:HO[(C₂H₄O)_(x)/(C₃H₆O)_(y)]—[C₃H₆O]_(z)—[(C₂H₄O)_(x)/(C₃H₆O)_(y)]Hwherein the sum of x, y and z is from between 125 and
 175. 6.Toothpastes according to claim 3, wherein nonionic surfactants, suitablefor said toothpastes, are represented by the structural formula:HO[(C₂H₄O)_(x)/(C₃H₆O)_(y)]—[C₃H₆O]_(z)—[(C₂H₄O)_(x)/(C₃H₆O)_(y)]Hwherein x=76, y=25 and z=56.
 7. Toothpastes, according claim 1,containing unreacted, calcium and phosphate components.
 8. Anaqueous-free, enamel protectant and enamel repair, toothpastescontaining stannous fluoride and calcium in a substantivity agentcomprising an emulsion of polydimethylsiloxane polymer at viscositiesfrom between about 10,000 cs and about 2.5 million cs as thediscontinuous phase in a nonionic poloxamer surfactant, continuous phasecontaining a linear polymeric polycarboxylates substantivity enhancer,wherein said nonionic surfactant is a surfactant selected from the groupconsisting of surfactants having the following, general, structuralformula:HO[(C₂H₄O)_(x)/(C₃H₆O)_(y)]—[C₃H₆O]_(z)—[(C₂H₄O)_(x)/(C₃H₆O)_(y)]Hwherein the sum of x, y and z is from between 125 and 175; with an EPFof at least 2.5 and ERF of at least 200, wherein: (a) Substantivity ofsaid stannous fluoride and calcium into biofilm present on enamel isenhanced through a shift in calcium binding from bidentate tomonodentate in the presence of stannous fluoride; (b) wherein thestannous fluoride is present in an amount of 400-1100 ppm; (c) whereinthe composition has a pH of 3-5.8; (d) wherein the calcium content is0.5-5.0%; (e) wherein the calcium is limited to one or more of calciumfumarate, calcium sulfate, calcium gluconate, and mixed sodium andcalcium salts of methyl/vinyl/ether/maleic copolymers thereof; and (f)wherein said nonionic poloxamer is selected from solid and liquid,nonionic poloxamers and combinations thereof.
 9. Toothpastes, accordingto claim 8, wherein nonionic poloxamer surfactants, suitable for saidtoothpastes, are represented by the structural formula:HO[(C₂H₄O)_(x)/(C₃H₆O)_(y)]—[C₃H₆O]_(z)—[(C₂H₄O)_(x)/(C₃H₆O)_(y)]Hwherein the sum of x, y and z is from between 125 and
 150. 10.Toothpastes, according to claim 8, wherein nonionic poloxamersurfactants, suitable for said toothpastes, are represented by thestructural formula:HO[(C₂H₄O)_(x)/(C₃H₆O)_(y)]—[C₃H₆O]_(z)—[(C₂H₄O)_(x)/(C₃H₆O)_(y)]Hwherein x=76, y=0 and z=56.
 11. Toothpastes, according claim 8,containing unreacted, calcium and phosphate components.
 12. Anaqueous-free, enamel protectant and enamel repair, toothpastes,featuring monodentate-bidentate bonding of calcium in the presence ofstannous fluoride; containing: stannous fluoride, calcium and phosphatecomponents, and a substantivity agent emulsion containing nonionicpoloxamer surfactant as the continuous phase and polydimethylsiloxanepolymer as the discontinuous phase; with an EPF of at least 2.5 and ERFof at least 200, wherein (a) Substantivity of said stannous fluoride andcalcium into biofilm present on enamel is enhanced through a shift incalcium binding from bidentate to monodentate in the presence ofstannous fluoride; (b) wherein the stannous fluoride is present in anamount of 400-1100 ppm; (c) wherein the composition has a pH of 3-5.8;(d) wherein the calcium content is 0.5-5.0%; (e) wherein the calcium islimited to one or more of calcium fumarate, calcium sulfate, calciumgluconate, and mixed sodium and calcium salts ofmethyl/vinyl/ether/maleic copolymers thereof, and (f) wherein saidnonionic poloxamer surfactant is selected from solid and liquid,nonionic poloxamers and combinations thereof.
 13. Toothpastes, accordingto claim 5, wherein said polydimethylsiloxane polymer discontinuousphase comprises up to 20% of said emulsion.
 14. An aqueous-free, enamelprotectant and enamel repair, toothpastes containing stable stannousfluoride and calcium on a substantivity agent substantive to biofilmcoated enamel, wherein said substantivity agent is selected from solidand liquid, nonionic poloxamers and combinations thereof, wherein: (a)substantivity of said stannous fluoride and calcium into said biofilm isenhanced by a substantivity enhancer and by a shift from bidentatebinding of calcium to monodentate in the presence of stable stannousfluoride; and (b) said stannous fluoride, upon release from saidsubstantivity agent, converts to the moiety CaF which effects EPF andERF values of at least 2.5 and at least 200, respectively; (c) whereinthe stannous fluoride is present in an amount of 400-1100 ppm; (d)wherein the composition has a pH of 3-5.8; (e) wherein the calciumcontent is 0.5-5.0%; and (f) wherein the calcium is limited to one ormore of calcium fumarate, calcium sulfate, calcium gluconate, and mixedsodium and calcium salts of methyl/vinyl/ether/maleic copolymersthereof.
 15. Toothpastes, according to claim 1, wherein said stannousfluoride, upon release from said substantivity agent, includes a Carmoiety in the presence of said calcium monodentate binding to saidbiofilm present on enamel.
 16. Toothpastes, according to claim 1,wherein the pH of said toothpastes, upon administration to enamel withbiofilm, is about
 3. 17. Toothpastes, according to claim 3, wherein thelevel of said substantivity agent and said substantivity enhancers isbetween about 0.5 and about 5% by wt. and about 0.1 and about 3% by wt.,respectively.
 18. Toothpastes, according to claim 3, wherein saidsubstantivity enhancer has the structural formula:

where m is an integer that provides weight between about 60,000 andabout 1,000,000.
 19. Toothpastes, according to claim 14, wherein theconcentration of polydimethylsiloxane is up to about 20% by wt. of saidemulsion.
 20. Toothpastes, according to claim 14, wherein: the ratio ofunreacted calcium and phosphate components is from between about 2 andabout 1, and the level of calcium and phosphate mixture in saidtoothpastes ranges from between about 0.2% and about 3%. 21.Toothpastes, according to claim 14, wherein said emulsion substantivityagent comprises from between about 0.5 and about 3.0 wt. percent of saidtoothpastes and said copolymer substantivity agent comprises frombetween about 0.5 and about 2.8 wt. percent of said toothpastes. 22.Toothpastes, according to claim 14, wherein: the pH of said toothpaste,upon exposure to saliva, is from between about 4 and about 8.